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P38 kinases mediate NLRP1 inflammasome activation after ribotoxic stress response and virus infection.
Jenster, Lea-Marie; Lange, Karl-Elmar; Normann, Sabine; vom Hemdt, Anja; Wuerth, Jennifer D; Schiffelers, Lisa D J; Tesfamariam, Yonas M; Gohr, Florian N; Klein, Laura; Kaltheuner, Ines H; Ebner, Stefan; Lapp, Dorothee J; Mayer, Jacob; Moecking, Jonas; Ploegh, Hidde L; Latz, Eicke; Meissner, Felix; Geyer, Matthias; Kümmerer, Beate M; Schmidt, Florian I.
Afiliación
  • Jenster LM; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany.
  • Lange KE; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany.
  • Normann S; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany.
  • vom Hemdt A; Institute of Virology, Medical Faculty, University of Bonn, Bonn, Germany.
  • Wuerth JD; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany.
  • Schiffelers LDJ; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany.
  • Tesfamariam YM; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany.
  • Gohr FN; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany.
  • Klein L; Department of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria, Australia.
  • Kaltheuner IH; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany.
  • Ebner S; Institute of Structural Biology, Medical Faculty, University of Bonn, Bonn, Germany.
  • Lapp DJ; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany.
  • Mayer J; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany.
  • Moecking J; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany.
  • Ploegh HL; Department of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria, Australia.
  • Latz E; Institute of Structural Biology, Medical Faculty, University of Bonn, Bonn, Germany.
  • Meissner F; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA.
  • Geyer M; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany.
  • Kümmerer BM; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany.
  • Schmidt FI; Institute of Structural Biology, Medical Faculty, University of Bonn, Bonn, Germany.
J Exp Med ; 220(1)2023 01 02.
Article en En | MEDLINE | ID: mdl-36315050
Inflammasomes integrate cytosolic evidence of infection or damage to mount inflammatory responses. The inflammasome sensor NLRP1 is expressed in human keratinocytes and coordinates inflammation in the skin. We found that diverse stress signals induce human NLRP1 inflammasome assembly by activating MAP kinase p38: While the ribotoxic stress response to UV and microbial molecules exclusively activates p38 through MAP3K ZAKα, infection with arthropod-borne alphaviruses, including Semliki Forest and Chikungunya virus, activates p38 through ZAKα and potentially other MAP3K. We demonstrate that p38 directly phosphorylates NLRP1 and that serine 107 in the linker region is critical for activation. NLRP1 phosphorylation is followed by ubiquitination of NLRP1PYD, N-terminal degradation of NLRP1, and nucleation of inflammasomes by NLRP1UPA-CARD. In contrast, activation of NLRP1 by nanobody-mediated ubiquitination, viral proteases, or inhibition of DPP9 was independent of p38 activity. Taken together, we define p38 activation as a unifying signaling hub that controls NLRP1 inflammasome activation by integrating a variety of cellular stress signals relevant to the skin.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Virosis / Proteínas Quinasas p38 Activadas por Mitógenos / Inflamasomas Límite: Humans Idioma: En Revista: J Exp Med Año: 2023 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Virosis / Proteínas Quinasas p38 Activadas por Mitógenos / Inflamasomas Límite: Humans Idioma: En Revista: J Exp Med Año: 2023 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos